Loading ...

MANCHESTER, England — Febuxostat (Uloric) did not appear to increase the risk for major adverse cardiovascular (CV) events (MACEs) when compared with no urate-lowering therapy (ULT) in people with gout, according to findings from a real-world, retrospective cohort study reported at the British Society for Rheumatology (BSR) 2025 Annual Meeting.

Using data primarily from the Clinical Practice Research Datalink (CPRD), UK researchers found that the composite primary outcome of MACEs — defined as myocardial infarction, ischemic stroke, heart failure hospitalization, unstable angina, revascularization, and cardiac mortality — occurred no more frequently among people who were treated with febuxostat than those who were not.

Although the rate of this primary outcome per 1000 person-years of treatment was initially higher in febuxostat users (66.01) than in allopurinol users (51.86) and in nonusers (40.13) using a univariate model, there was no statistically significant difference after multivariate adjustment. This included adjustment for patient age, sex, previous CV disease, ethnicity, hypercholesterolemia, hypertension, diabetes, chronic kidney disease, smoking status, social deprivation, body mass index, smoking status, co-prescriptions in the preceding 2 months, and the number of gout consultations and hospitalizations in the previous 12 months.

Indeed, the hazard ratio comparing febuxostat use with no ULT was 1.07 (95% CI, 0.99-1.16), reported study investigator Richard Partington, MBChB, MSc, PhD, a general practitioner in Morecambe, England, and National Institute for Health and Care Research Clinical Lecturer at Keele University, Staffordshire, England. In comparison, the hazard ratio comparing allopurinol use with no ULT was 1.19 (95% CI, 1.16-1.22).

CV Concerns Raised Then Allayed

Concern about the CV safety of ULT with febuxostat rose following the 2018 publication of results from the US Food and Drug Administration–mandated postmarketing trial called CARES, which was undertaken when studies in the drug development process for febuxostat suggested a modestly higher rate of CV events with febuxostat than with allopurinol. Although no difference between the drugs was seen in CARES for the primary endpoint of a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization, a secondary analysis suggested there was a higher rate of all-cause and CV mortality among febuxostat- vs allopurinol-treated patients.

In 2020, the results of the Febuxostat Versus Allopurinol Streamlined Trial (FAST) were published and appeared to exonerate febuxostat of any excess CV risk in comparison to allopurinol. 

In 2021, a real-world claims data study from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, backed up the FAST results: There was no excess CV risk associated with febuxostat relative to allopurinol, even in those with preexisting CV disease. 

However, limitations of the FAST and CARES studies included the lack of a placebo group. Partington and his associates thus wanted to see if there was any excess risk of receiving febuxostat vs no ULT.

Probing CPRD for Validation

In 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom changed its position on when to used febuxostat in people who had experienced prior CV events. Rather than advising completely against it, the agency advised caution over its use.

Partington also noted that the National Institute for Health and Care Excellence recommended febuxostat as first-line treatment for gout in the United Kingdom.

To examine the CV risk associated with febuxostat use relative to allopurinol use further and include a control arm of no ULT, Partington and colleagues obtained data from several UK-based databases: The primary care CPRD for cases of gout, the Hospital Episodes Statistics and Office for National Statistics for data on hospitalizations and deaths associated with gout, and patient-level Index of Multiple Deprivation.

In all, data on more than 305,000 individuals aged older than 40 years with a diagnosis of gout from December 2008 to March 2021 were included in the analysis, of whom 7378 had been treated with febuxostat, 97,940 with allopurinol, and 200,387 had received no ULT.

Around three fifths of the study population were men, and the mean age was approximately 65 years.

Prophylaxis Is Key

The use of recommended co-prescription strategies alongside ULT may be key to attenuating any CV risks that may be associated with either febuxostat or allopurinol use, Partington said. 

The risk for MACEs with prophylaxis for acute gout attacks (consisting of colchicine, nonsteroidal anti-inflammatory drugs, or corticosteroids) was similar for both febuxostat (adjusted hazard ratio [aHR], 0.81; 95% CI, 0.64-1.02) and allopurinol (aHR, 0.87; 95% CI, 0.72-1.06), and the risk for MACEs without prophylaxis was significantly elevated for both febuxostat (aHR, 1.12; 95% CI, 1.02-1.22) and allopurinol (aHR, 1.27; 95% CI, 1.24-1.32).

These data emphasize the importance of prescribing prophylaxis when commencing ULT, Partington observed.

‘Reassuring’ Results

“These findings provide reassurance about using febuxostat in people with gout,” Partington said.

“Our findings support the MHRA position [that] caution is required if prescribing febuxostat in patients with preexisting major cardiovascular disease,” he said.

Commenting to Medscape Medical News, abstract session co-chair Max Yates, MBBS, PhD, who is an honorary consultant rheumatologist for Norwich and Norfolk University Hospitals NHS Foundation Trust and a clinical associate professor at the University of East Anglia, both in Norwich, England, agreed that these data were “largely reassuring.”

Since febuxostat first became available in 2008, its use has widened from being prescribed only in secondary care for the most severe phenotypes of gout to more general use in primary care, Yates said.

The fact that there is “not a big increase” in the data on CV risk with wider use is good because “if you’re a cynic, you might think, well, when you take the brake off on who is allowed to prescribe, you may have inappropriate prescription, but that does not seem to be the case,” said Yates.

“We know that febuxostat works very well, it’s very powerful in terms of its urate-lowering ability, which is obviously very beneficial for patients,” Yates added. 

He observed that MHRA guidance still stipulates that caution needs to be exercised when prescribing febuxostat to people with a history of CV disease, but based on these data, presumably that guidance is being followed because an excess in mortality has not been seen.

The study was independently supported. Partington and Yates reported having no relevant financial relationships.

Sara Freeman is a freelance medical journalist based in London, England.